Lozenge for the modified releasing of active substances in the gastrointestinal tract

ABSTRACT

A pharmaceutical lozenge for the modified release of active compounds in the gastrointestinal tract is described, with active-compound-containing particles which have a first coating controlling the release and a further, outer coating with saliva-resistant properties. The first coating, which controls the release of active compound, can have release-delaying or enteric properties.

[0001] The invention relates to a pharmaceutical lozenge for themodified release of active compounds in the gastrointestinal tract, withactive-compound-containing particles which have a first coatingcontrolling the release and a further, outer coating withsaliva-resistant properties.

[0002] Orally administrable presentation forms having modified activecompound release can serve various therapeutic aims. The most frequentaims are the protection of the gastric mucosa from a harmful activecompound or the protection of the active compound from the acidic mediumin the stomach on the one hand, which is brought about by entericcoatings; moreover the control of the release rate over a relativelylong time, which can be achieved by various release-delaying measuresand leads to plasma levels with relatively low variations, a bettertolerability as a result and a longer efficacy of the administration.

[0003] A formulation with modified active-compound release cannot beequally easily developed in the case of all pharmacologically suitableactive substances. As a rule, it necessitates a number of additives withthe aid of which the desired effects can be achieved. These additivescorrespondingly clearly increase the mass of the presentation form. Inpresentation forms with prolonged release of active compound, the doseto be administered is additionally increased compared to a simplepresentation form. In the case of various active compounds, on accountof their dose, no presentation forms having prolonged release of activecompound could be developed using the possibilities known until now,since they could not be swallowed in the form of a capsule or tabletbecause of the resulting dimensions. Thus various antibiotics, forexample, must still be orally administered three to four times dailyalthough it is known that in the case of administration more than twicedaily the reliability of taking by patients is low. In the case ofantibiotics, the non-delayed-release single dose is frequently already500 to 1000 mg, which together with the auxiliaries necessary forpharmaceutical formulation leads to capsules or tablets which can onlybe swallowed with difficulty. A delayed-release preparation prepared onthe basis of conventional techniques with more than 1000 mg of activecompound and an increased content of auxiliaries can virtually no longerbe swallowed.

[0004] The provision of a presentation form which is easy and pleasantto take with modified release of active compound, which is also suitablefor active compounds which have to be taken in high single doses, isdesirable.

[0005] According to the invention, the problem of the taking of highdoses should first of all be solved by administering a multiparticulateactive compound preparation which is compressed to give a lozenge, whoseparticles are individually coated to achieve a modified release. Thecoated particles are released in finely divided form on sucking thetablet in the mouth and can be easily swallowed with the saliva.

[0006] The presentation form of the lozenge has been known for a longtime and is frequently used in order to deliver active compounds to thediseased oral and pharyngeal mucosa. The lozenge can also be suitablefor systemically active substances if the substances have a pleasanttaste and are to be absorbed without delay. For the solution of theproblem, the presentation form of the lozenge is employed, since it isable to accommodate more active-compound and auxiliary mass without lossof its administrability than a tablet intended for swallowing. Lozengeshaving a mass of more than 4 g are on the market and are apparentlyaccepted by patients without problem.

[0007] In principle, the prior art allows the compression of coatedparticles having modified release of active compound, although theintended use according to the invention with itsadvantages—administration as a lozenge with suitability even for highdoses of active compound—was neither recognized nor described as asolution of the problem presented above.

[0008] Thus the Patent Applications EP 153 104 and EP 355 247 teach, forexample, the compression of release-delaying coated particles containingactive compound to give tablets, a process which is also described inother sources. Moreover, the U.S. Pat. No. 5,464,632 discloses a rapidlydisintegrating tablet intended for sucking or for disintegration in themouth, which contains the active compound optionally in the form ofcoated particles for modified release. However, with this tablet in thecase of disintegration in the mouth it is to be expected that portionsof the active compound have already been released through the coating ofthe particles into the oral cavity and in the course of this leavebehind an adverse taste impression.

[0009] Analogously, the presentation form of the lozenge, as is claimedin the present invention, does also solve, on the one hand, the problemof the administrability of relatively large amounts of active compoundand auxiliaries, but on the other hand creates new problems. For onething, in the case of enteric-coated particles the coatings are exposedto the pH-neutral saliva, as a result of which they prematurelydisintegrate and can no longer achieve the desired protective effect inthe stomach. For another thing, in the case of particles which areprovided with release-delaying coatings, portions of the active compoundhave already been released in the oral cavity by diffusion, which is notacceptable, in particular in the case of unpleasantly tastingsubstances.

[0010] A need therefore exists for a further improved presentation formhaving modified release of active compound for administration of highdoses of active compound, which does not have the disadvantagesmentioned. This object, on which the invention is based, is achieved bya pharmaceutical presentation form according to one of the two mainclaims: in addition to the special design as a lozenge, the tabletaccording to the invention overcomes the disadvantages of the prior artin that its active compound is present in the form of doubly ortwo-layer coated particles, a first, inner coating serving for therelease of the modified active compound, while a further, externalcoating is saliva-resistant, but dissolves in the acidic medium of thestomach and thereby ensures that during the sucking of the tablet activecompound is not released into the oral cavity. The first, inner coatingof the particles can modify the release of active compound according toone of the two main claims either in that the release commences onlyafter the gastric passage of the particle, or it can be designed as amembrane which is insoluble in the gastric and intestinal juice, butthrough which the active compound can slowly diffuse outwards and bereleased with a delay.

[0011] According to the invention, the active-compound-containingparticles are pressed together with suitable auxiliaries to givelozenges which, owing to their composition, slowly erode in the mouthand in the course of this release the particles into the saliva. Thesaliva containing the coated particles is then swallowed.Self-experiments showed that particles of up to approximately 100-200 μmin diameter are perceived to be only moderately troublesome onswallowing.

[0012] Film-forming polymers which can be employed for the production ofa saliva-resistant coating are known to the person skilled in the art.Frequently, a copolymer based on dimethylaminoethyl methacrylate andneutral methacrylic acid esters having the trade name Eudragit E (Röhm)is employed for this purpose. The basic character of thedimethylaminoethyl methacrylate provides for solubility in the acidicmedium, such as, for example, in the gastric juice, while the solubilityin the relatively neutral saliva is rather low. If the thickness of thefilm is suitable, a coating can therefore be produced using thiscopolymer which resists disintegration in the saliva for a longer time,but which dissolves rapidly in the stomach. Alternatively, all otherfilm-forming polymers which have a markedly better solubility in thegastric juice than in the saliva can be used for this purpose.

[0013] Release-delaying film coatings are widespread in the technologyof solid oral presentation forms. The polymers employed for thistypically have a low solubility in aqueous media both at acidic and atneutral to basic pHs. With sufficient thickness and mechanical strengthof the film coating, this dissolves neither in the saliva nor in thegastric or intestinal juice. On the other hand, the thickness must notbe too great, since the film coating must allow the diffusion of waterinto the active compound reservoir, where the active compound iscontinuously dissolved and diffuses outwards through the coating indissolved form. A large number of polymers have been employed for thispurpose; examples which may be mentioned are: polymers from the groupconsisting of the cellulose esters, such as, for example, celluloseacetate, representatives of the cellulose ethers group, such as, forexample, ethylcellulose, certain poly(meth)acrylic acid derivatives,e.g. Eudragit RL or RS (Röhm) and certain polyvinyl derivatives such aspolyvinyl acetate.

[0014] The polymers typically used for the preparation of film coatingswhich are resistant to gastric juice but soluble in small intestinaljuice have an extremely low solubility in the acidic medium withmarkedly better solubility in the neutral pH range. These properties areseen especially in those polymers which contain acidic groups which arepresent in undissociated form in the gastric juice. Examples which maybe mentioned are: hemiesters of divalent acids such as succinic orphthalic acid with cellulose ethers, cellulose esters, polyvinylderivatives, carboxymethylcelluloses or poly(meth)acrylic acids, such asare contained in Eudragit L or S (Röhm).

[0015] Elasticity and strength of the film coatings of the particles area prerequisite for the functionality of the pharmaceutical form, sincethe coatings must not be damaged by the strong mechanical stress duringcompression or tabletting; at least the predominant majority of theparticles contained in the lozenge should have two intact coating layerswithin the meaning of the invention. It is known to the person skilledin the art that the elasticity, flexibility and strength of the polymerfilms is dependent on the polymer type, molecular weight, degree ofsubstitution of the film-forming agents employed, but also on the natureand amount of the additives employed. In particular, plasticizers oradditives employed for other purposes, but which have a plasticizingaction, have a considerable effect on the mechanical film properties.For most of the polymers which can be employed within the meaning of theinvention, the prior art knows suitable plasticizers for the productionof certain mechanical properties; the person skilled in the art is ableby means of suitable experiments to determine the optimum amount ofplasticizer for the purpose of the tabletting according to the inventionof coated particles, which can differ completely from the amountrecommended for other purposes.

[0016] Two examples should serve to illustrate possible embodiments ofthe invention which, however, only have illustrative character; theperson skilled in the art is able to develop further examples usingdifferent recipes and preparation processes.

EXAMPLE 1

[0017] Lozenges of enteric-coated ibuprofen particles comprising 600 mgof ibuprofen

[0018] Ibuprofen micropellets are first prepared by granulating,extruding and spheronizing. For this, 700 g of ibuprofen, 180 g ofmicrocrystalline cellulose and 120 g of lactose monohydrate are mixed ina powder blender and then made into a paste in a suitable kneader mixerwith addition of n g of water to give a mass having a kneadableconsistency. The mass is extruded through a specially made perforateddisc having a hole diameter of 300 μm using an extruder, e.g. asingle-screw extruder of the E 40/10 D type (Gabler), cut and, ifpossible, rounded in the on-line process, e.g. in a spheronizer of thetype (Gabler) R 250. The micropellets are then dried in a dryer to aresidual moisture of about 2-3%, which can be carried out in a suitablefluidized bed apparatus, but preferably in the apparatus intended forthe coating of the pellets, e.g. the fluidized bedgranulator/dryer/coater of the Uni-Glatt type (Glatt). For theproduction of the first, enteric-coating, the pellets are sprayed intothe fluidized bed via a two-substance nozzle at about 1-2 bar in thetop-spray arrangement and at a spray velocity of 10 ml/min with adispersion of 95 g of Eudragit® L30 D-55, 45 g of Eudragit® NE 30 D(both Röhm), 8 g of triethyl citrate, 12 g of polyethylene glycol 6000,20 g of talc and 90 g of water up to a dry weight increase of 12%. Asuitable spray temperature is 38-43°C., and subsequent drying at 30-35°C. should take place.

[0019] The enteric-coated particles prepared in this way are thenprovided according to the invention with a second, saliva-resistantcoating. Alternatively, the production of the saliva resistance can alsobe carried out without transition by means of a change in the spraymedium in the preceding process. A suitable spray solution for this iscomposed of 240 g of Eudragit® E 12.5, 18 g of polyethylene glycol 6000,12 g of microcrystalline cellulose, 12 g of magnesium stearate and 220 gof acetone. It can be sprayed into the apparatus described above at thesame pressure and the same spray velocity, but preferably at atemperature reduced to about 30° C. The spray process is complete with aweight increase in the pellets of 11%.

[0020] After the subsequent drying, the particles now provided with twocoatings are compressed to give lozenges. For this, 1066 g ofpellets—these contain 600 g of ibuprofen —are mixed in a powder blenderwith 260 g of sorbitol (a directly tablettable quality is necessary), 2g of colloidal silica, 28 g of stearic acid and 11 g of magnesiumstearate and pressed in a tablet press to give tablets weighing 1367 mg,e.g. with a diameter of 18 mm.

EXAMPLE 2

[0021] Lozenges of release-delaying coated ibuprofen particlescomprising 600 mg of ibuprofen

[0022] The preparation is carried out analogously to Example 1 with theassumption that a dispersion of 110 g of Eudragit RS 30 D, 25 g of talc,28 g of triethyl citrate and 15 g of polyethylene glycol 6000 is usedfor the production of the release-modifying coating.

[0023] These working examples illustrate the principle of the invention;depending on prioritization of the product properties, e.g. low particlesizes for the sensory improvement of the sucking or disintegrationproperties of the tablet or lower auxiliary contents for the reductionof the production costs, they can be markedly optimized in the directionof one of the target parameters.

What is claimed is:
 1. Pharmaceutical lozenge pressed from pulverulentor granular press material, characterized in that the press materialcontains an active-compound preparation in the form of at leasttwo-layer coated particles in addition to customary auxiliaries suitablefor the production of lozenges, an outer coating layer beingsaliva-resistant, but soluble in gastric juice, and an inner coatinglayer being largely disintegration-resistant in aqueous media, butallowing a delayed release of active compound by diffusion. 2.Pharmaceutical lozenge pressed from pulverulent or granular pressmaterial, characterized in that the press material contains anactive-compound preparation in the form of at least two-layer coatedparticles in addition to customary auxiliaries suitable for theproduction of lozenges, an outer coating layer being saliva-resistant,but soluble in gastric juice, and an inner coating layer being gastricjuice-resistant, but soluble in the small intestine.
 3. Pharmaceuticallozenge according to claim 1 or 2 , characterized in that thesaliva-resistant, but gastric juice-soluble coating layer contains asfilm-forming agent one or more polymers from the group consisting of thedimethylaminoethyl methacrylates and the methacrylic acid esters. 4.Pharmaceutical lozenge according to claim 1 , characterized in that thecoating layer delaying the release of active compound contains asfilm-forming agent one or more polymers from the group consisting of thecellulose ethers, cellulose esters, polyacrylic acid derivatives,polymethacrylic acid derivatives and polyvinyl derivatives. 5.Pharmaceutical lozenge according to claim 2 , characterized in that thegastric juice-resistant coating layer contains as film-forming agent oneor more polymers from the group consisting of the cellulose ether,cellulose ester or polyvinyl acetate phthalates or succinates, thecarboxymethylcelluloses, the polyacrylic acid derivatives and thepolymethacrylic acid derivatives.
 6. Pharmaceutical lozenge according toone of the preceding claims, characterized in that the film coatings, inaddition to film-forming polymers, contain those pharmaceuticallyacceptable auxiliaries which are able to increase the flexibility of thefilm coatings.
 7. Process for the production of pharmaceutical lozengesaccording to one of the preceding claims, characterized in that in afirst process step, by means of an agglomeration process, amultiparticulate preparation is prepared from a mixture of activecompound and suitable auxiliaries, whose particles are coated in asecond process step in a spray application process first with anactive-compound-delaying or enteric film coating, then with asaliva-resistant, but gastric juice-soluble film coating, and compressedtogether with further auxiliaries in a tablet machine in a third processstep to give lozenges.
 8. Pharmaceutical lozenge pressed frompulverulent or granular press material wherein the press materialcontains an active-compound preparation in the form of at leasttwo-layer coated particles in addition to customary auxiliaries suitablefor the production of lozenges, an outer coating layer beingsaliva-resistant, but soluble in gastric juice, and an inner coatinglayer being largely disintegration resistant in aqueous media, butallowing a delayed release of active compound by diffusion. 9.Pharmaceutical lozenge pressed from pulverulent or granular pressmaterial wherein the press material contains an active-compoundpreparation in the form of at least two-layer coated particles inaddition to customary auxiliaries suitable for the production oflozenges, an outer layer being saliva-resistant, but soluble in gastricjuice, and an inner coating layer being gastric juice-resistant, butsoluble in the small intestine.
 10. The pharmaceutical lozenge of claim8 wherein the saliva-resistant, but gastric juice-soluble coating layercontains a film-forming agent comprising one or more polymers selectedfrom the group consisting of the dimethylaminoethyl methacrylates andthe methacrylic acid esters.
 11. The pharmaceutical lozenge of claim 9wherein the saliva-resistant, but gastric juice-soluble layer coatinglayer contains a film-forming agent comprising one or more polymersselected from the group consisting of the dimethylaminoethylmethacrylates and the methacrylic acid esters.
 12. The pharmaceuticallozenge of claim 8 wherein the coating layer delaying the release ofactive compound contains a film-forming agent comprising one or morepolymers selected from the group consisting of the cellulose ethers,cellulose esters, polyacrylic acid derivatives, polymethacrylic acidderivatives and polyvinyl derivatives.
 13. The pharmaceutical lozenge ofclaim 9 wherein the gastric juice-resistant coating layer contains afilm-forming agent comprising one or more polymers selected from thegroup consisting of the cellulose ether, cellulose ester or polyvinylacetate phthalates or succinates, the carboxymethylcelluloses, thepolyacrylic acid derivatives and the polymethacrylic acid derivatives.14. The pharmaceutical composition of claim 10 comprising film coatingswhich in addition to the film-forming polymers further comprisepharmaceutically acceptable auxiliaries which increase the flexibilityof the film coatings.
 15. The pharmaceutical composition of claim 11comprising film coatings which in addition to the film-forming polymersfurther comprise pharmaceutically acceptable auxiliaries which increasethe flexibility of the film coatings.
 16. The pharmaceutical compositionof claim 12 comprising film coatings which in addition to thefilm-forming polymers further comprise pharmaceutically acceptableauxiliaries which increase the flexibility of the film coatings.
 17. Thepharmaceutical composition of claim 13 comprising film coatings which inaddition to the film-forming polymers further comprise pharmaceuticallyacceptable auxiliaries which increase the flexibility of the filmcoatings.
 18. Process of the production of a pharmaceutical lozenge ofclaim 8 comprising: (a) producing a multiparticulate preparation from amixture of active compound and suitable auxiliaries by an agglomerationprocess; (b) coating the particles of said multiparticulate preparationproduced in step (a) in a spray application first with anactive-compound-delaying or enteric film coating and then with asaliva-resistant, but gastric juice-soluble film coating; and (c)compressing the coated particles produced in step (b) with furtherauxiliaries in a tablet machine to produce a lozenge.
 19. Process of theproduction of a pharmaceutical lozenge of claim 9 comprising: (a)producing a multiparticulate preparation from a mixture of activecompound and suitable auxiliaries by an agglomeration process; (b)coating the particles of said multiparticulate preparation produced instep (a) in a spray application first with an active-compound-delayingor enteric film coating and then with a saliva-resistant, but gastricjuice-soluble film coating; and (c) compressing the coated particlesproduced in step (b) with further auxiliaries in a tablet machine toproduce a lozenge.